Therapeutic peptides are widely used in medical practise. Pharmaceutical compositions of such therapeutic peptides must have a shelf life of several years in order to be suitable for common use. However, peptide compositions are inherently unstable due to sensitivity towards chemical and physical degradation. Chemical degradation involves change of covalent bonds, such as oxidation, hydrolysis, racemization or crosslinking. Physical degradation involves conformational changes relative to the native structure of the peptide, i.e. secondary and tertiary structure, such as aggregation, precipitation or adsorption to surfaces.
Glucagon has been used for decades in medical practise within diabetes and several glucagon-like peptides are being developed for various therapeutic indications. The preproglucagon gene encodes glucagon as well as glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2). GLP-1 analogs and derivatives as well as the homologous lizard peptide, exendin-4, are being developed for the treatment of hyperglycemia within type 2 diabetes. GLP-2 is potentially useful in the treatment of gastrointestinal diseases. However, all these peptides encompassing 29-39 amino acids have a high degree of homology and they share a number of properties, notably their tendency to aggregate and formation of insoluble fibrils. This property seems to encompass a transition from a predominant alpha-helix conformation to beta-sheets (Blundell T. L. (1983) The conformation of glucagon. In: Lefébvre P. J. (Ed) Glucagon I. Springer Verlag, pp 37-55, Senderoff R. I. et al., J. Pharm. Sci. 87 (1998)183-189). Aggregation of the glucagon-like peptides are mainly seen when solutions of the peptides are stirred or shaken, at the interface between solution and gas phase (air), and at contact with hydrophobic surfaces such as Teflon®.
Thus, pharmaceutical compositions of the glucagon-like peptides must often be added various excipients in order to improve the stability. Shelf life of liquid parenteral formulations of these peptides must be at least a year, preferably longer. The in-use period where the product may be transported and shaken daily at ambient temperature preferably should be several weeks. Thus, there is a need for pharmaceutical compositions of glucagon-like peptides which have improved stability.
We have unexpectedly found human serum albumin to be an excipient that can improve the stability of pharmaceutical compositions containing a glucagon-like peptide.
WO 99/43341 and WO 03/02136 discloses certain pharmaceutical formulations comprising GLP-1 derivatives. WO 00/37098 discloses formulations comprising GLP-1 at pH from 8.2 to 8.8. WO 00/41546 discloses formulations comprising exendin-4, a buffer, an isotonic agent and pH between 3 and 7.
WO 01/10446 discloses formulations of the cytotoxic drug estramustine phosphate comprising albumin to protect against side-effects at the site of injection. WO 90/12029 discloses the use of serum albumin in lyophilized pharmaceutical formulations. WO 02/72135 discloses liquid preparations of interferon a comprising serum albumin.
The present invention is based on the finding that pharmaceutical compositions of glucagon-like peptides comprising human serum albumin have increased stability.